Obsessive-compulsive disorder (OCD) is a severe mental disorder that is a significant public health problem. The neurobiology of OCD remains unclear because it is difficult to study brain pathways in living people, and neither post-mortem studies nor validated animal models exist. We propose to build a novel partnership between basic and clinical researchers to develop animal models of specific neurobiological features of OCD that can guide future human studies. Our ultimate goal is to elucidate the neurobiology of OCD and to spearhead novel treatment approaches. This R24 application will enable us to develop the laboratory and scientific resources to be able to conduct this type of translational work. As a first step, we will examine the role of sensorimotor gating deficits and the 5-HT1B receptor (known as the 5-HT1DJ3 receptor in the human literature), which have both been implicated in OCD. Our preliminary findings in mice indicate that acute 5-HT1B agonist challenge leads to sensorimotor gating deficits as measured by decreased prepulse inhibition (PPI) and repetitive behavior (i.e., locomotor stereotypy); these effects are blocked by chronic pretreatment with the serotonin reuptake inhibitor (SRI) fluoxetine. OCD patients may also have PPI deficits and do have repetitive behavior. This R24 will enable us to develop the resources needed to test the working hypothesis that increased 5-HT1B function leads to PPI deficits and locomotor stereotypy in mice and may contribute to the PPI deficits and repetitive behavior in OCD. Specifically, we will: 1) generate transgenic mice with human 5-HT1B receptors; 2) examine in these mice the effects of OCD treatments on the behaviors induced by 5-HT1B agonists (decreased PPI and locomotor stereotypy) and on 5-HT1B receptor expression and functional coupling in the brain; and 3) examine whether PPI deficits in OCD patients are associated with clinical features and/or SRI treatment response. In the process, we will lay the foundation for future translational research on other aspects of the serotonin system as they relate to the neurocircuitry of OCD. We expect that our work will lead to a collaborative R01 or Translational Research Center application that will integrate animal and human work in the quest for novel treatments to reduce the burden of OCD. Thus, our application is directly relevant to NIMH's mission: to improve mental health by advancing the scientific understanding of a severe mental illness like OCD. [unreadable] [unreadable] [unreadable]